MEGAKARYOPOIESIS AND ITS REGULATION
MEGAKARYOPOIESIS
It is the process of proliferation, dedifferentiation and maturation of megakaryocytes in bone marrow under the influence of growth factors and hormones.
• Megakaryocytes are rare cells within the bone marrow and consist of only 0.1% of the total nucleated cells.
• In healthy individual the bone marrow produces 1×10^11 platelets per day.
• Bone marrow can increases platelet production 10 to 20-fold on increased demand or stimulation of exogenous thrombopoiesis-stimulating drugs.
• Platelets are produced in the bone marrow from the same stem cell (PHSC)
• Stem cell differentiated into progenitor cell erythroid and myeloid lineages (CFU-GEMM)
• The bipotential myeloid-erythroid progenitor cell (MEP) ultimately gives rise to precursor cells committed to megakaryocytic development.
• Committed megakaryocytes progenitor differentiate into BFU-Mk and CFU-Mk.
• Morphologically, early progenitor cells appear as small indistinguishable lymphoid-like cells
• The transit time from megakaryocyte progenitor cell to release of platelets into the circulation is from 4-7 days.
• Megakaryocytes are found primarily in the vascular niche where they physically attach to endothelial cells lining the sinusoidal vessels.
• Marrow stromal cells produce both positive and negative regulators of megakaryocyte growth factors.
• Stromal cell-derived factor-1 (SDF-1) also contributes to megakaryopoiesis by enhancing TPO induced megakaryocyte growth and endothelial adhesion within the marrow microenvironment
STAGES Of MEGAKARYOPOIESIS
• The earliest identifiable cell of this lineage is the megakaryoblast.
• Morphologically it is not recognizable it is identified cytochemically by their expression of megakaryocyte specific markers, such as glycoprotein IIb/IIIa or platelet peroxidase.
• Endomitosis begins in megakaryoblasts and is completed by the end of stage megakaryocytes
• Endomitosis is a unique form of mitosis in which the cell’s DNA content doubles, but cell division and nuclear division do not take place.
• Repetitive cycles result in cells that become polyploid with the increased DNA content contained within a single nuclear envelope.
• Polyploid cells contain exact multiples of the normal DNA content (normally 2N) and can range from 4N to 64N or higher.
• The 16N stage is the most common ploidy stage in adult humans.
• Cytoplasmic maturation can be initiated at nuclear ploidy levels of 8N or more.
• Megakaryocyte development are divided into four stages as described on Romanowsky-stained bone marrow smears.
• The major criteria differentiating these stages include the quantity and characteristics of the cytoplasm and the size, lobulation, and chromatin pattern of the nucleus.
• Mature megakaryocyte develops an internal membrane system of channels called the demarcation membrane system (DMS).
• It is derived by invagination of the megakaryocyte’s outer membrane and eventually develops into a highly branched, interconnected system of channels that maintain open communication with the extracellular space.
• Megakaryocytes also produce a second extensive membranous system, the dense tubular system (DTS), which, unlike the DMS, does not communicate with the cell surface.
• DMS becomes extensive, small areas of the megakaryocyte cytoplasm are compartmentalized.
• These areas eventually become the platelets.
THROMBOPOIESIS
• It is the process of platelets formation from megakaryocyte in bone marrow.
• Platelets form by fragmentation of megakaryocyte cytoplasm.
• Platelets released from membrane extensions of megakaryocytes in groups called proplatelets.
• Mature megakaryocytes are typically situated near the marrow sinus endothelial cells and shed platelets directly into the marrow sinuses.
• Each megakaryocyte is estimated to give rise to 1000–3000 platelets, depending on the ploidy of the parent megakaryocyte.
REGULATION OF MEGAKARYOPOIESIS
• Several cytokines and growth factors regulate megakaryopoiesis.
• Interleukin-3 (IL-3), GM-CSF, stem cell factor, and Flt ligand influence the progenitor stages of megakaryocytes to proliferate.
• Interleukin-6 and -11 also affect megakaryocyte development, particularly the maturation phases.
• The key factor that regulating megakaryocyte and platelet development is thrombopoietin (TPO).
• TPO influences all stages of megakaryocyte production from the committed megakaryocyte stem cell to the release of mature platelets from the bone marrow.
• TPO also plays an important role in hematopoietic stem cell survival, self-renewal, and expansion.
• c-Mpl is receptor for TPO on megakaryocyte inactivating mutations of c-Mpl lead to congenital amegakaryocytic thrombocytopenia.
• Activating mutations of c-Mpl lead to familial thrombocytosis.
